Delivery of sedative-hypnotics through an inhalation route

ABSTRACT

The present invention relates to the delivery of sedative-hypnotics through an inhalation route. Specifically, it relates to aerosols containing sedative-hypnotics that are used in inhalation therapy. In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of a sedative-hypnotic. In a method aspect of the present invention, a sedative-hypnotic is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of a sedative-hypnotic, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. In a kit aspect of the present invention, a kit for delivering a sedative-hypnotic through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of a sedative-hypnotic; and, b) a device that forms a sedative-hypnotic containing aerosol from the composition, for inhalation by the mammal.

[0001] This application claims priority to U.S. provisional applicationSerial No. 60/294,203 entitled “Thermal Vapor Delivery of Drugs,” filedMay 24, 2001, Rabinowitz and Zaffaroni, the entire disclosure of whichis hereby incorporated by reference. This application further claimspriority to U.S. provisional application Serial No. 60/317,479 entitled“Aerosol Drug Delivery,” filed Sep. 5, 2001, Rabinowitz and Zaffaroni,the entire disclosure of which is hereby incorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the delivery ofsedative-hypnotics through an inhalation route. Specifically, it relatesto aerosols containing sedative-hypnotics that are used in inhalationtherapy.

BACKGROUND OF THE INVENTION

[0003] There are a number of compositions currently marketed assedative-hypnotics. The compositions contain at least one activeingredient that provides for observed therapeutic effects. Among theactive ingredients given in sedative-hypnotic compositions are zolpidem,zaleplon, and zopiclone.

[0004] It is desirable to provide a new route of administration forsedative-hypnotics that rapidly produces peak plasma concentrations ofthe compound. The provision of such a route is an object of the presentinvention.

SUMMARY OF THE INVENTION

[0005] The present invention relates to the delivery ofsedative-hypnotics through an inhalation route. Specifically, it relatesto aerosols containing sedative-hypnotics that are used in inhalationtherapy.

[0006] In a composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight of asedative-hypnotic. Preferably, the particles comprise at least 10percent by weight of a sedative hypnotic. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent or 99.97 percent by weight of a sedative hypnotic.

[0007] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0008] Typically, the particles comprise less than 10 percent by weightof sedative-hypnotic degradation products. Preferably, the particlescomprise less than 5 percent by weight of sedative-hypnotic degradationproducts. More preferably, the particles comprise less than 2.5, 1, 0.5,0.1 or 0.03 percent by weight of sedative-hypnotic degradation products.

[0009] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0010] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0011] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

[0012] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0013] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

[0014] Typically, the aerosol is formed by heating a compositioncontaining a sedative-hypnotic to form a vapor and subsequently allowingthe vapor to condense into an aerosol.

[0015] In another composition aspect of the present invention, theaerosol comprises particles comprising at least 5 percent by weight ofzaleplon, zolpidem or zopiclone. Preferably, the particles comprise atleast 10 percent by weight of zaleplon, zolpidem or zopiclone. Morepreferably, the particles comprise at least 20 percent, 30 percent, 40percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weightof zaleplon, zolpidem or zopiclone.

[0016] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μg.

[0017] Typically, the particles comprise less than 10 percent by weightof zaleplon, zolpidem or zopiclone degradation products. Preferably, theparticles comprise less than 5 percent by weight of zaleplon, zolpidemor zopiclone degradation products. More preferably, the particlescomprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight ofzaleplon, zolpidem or zopiclone degradation products.

[0018] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0019] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0020] Typically, the aerosol has an inhalable aerosol drug mass densityof between 0.5 mg/L and 40 mg/L. Preferably, the aerosol has aninhalable aerosol drug mass density of between 1 mg/L and 20 mg/L. Morepreferably, the aerosol has an inhalable aerosol drug mass density ofbetween 1 mg/L and 10 mg/L.

[0021] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL or 10⁸particles/mL.

[0022] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0023] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

[0024] Typically, the aerosol is formed by heating a compositioncontaining zaleplon, zolpidem or zopiclone to form a vapor andsubsequently allowing the vapor to condense into an aerosol.

[0025] In a method aspect of the present invention, one of asedative-hypnotic is delivered to a mammal through an inhalation route.The method comprises: a) heating a composition, wherein the compositioncomprises at least 5 percent by weight of a sedative-hypnotic, to form avapor; and, b) allowing the vapor to cool, thereby forming acondensation aerosol comprising particles, which is inhaled by themammal. Preferably, the composition that is heated comprises at least 10percent by weight of a sedative-hypnotic. More preferably, thecomposition comprises at least 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of a sedative-hypnotic.

[0026] Typically, the particles comprise at least 5 percent by weight ofa sedative-hypnotic. Preferably, the particles comprise at least 10percent by weight of a sedative-hypnotic. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of asedative-hypnotic.

[0027] Typically, the condensation aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200 μg.

[0028] Typically, the particles comprise less than 10 percent by weightof sedative-hypnotic degradation products. Preferably, the particlescomprise less than 5 percent by weight of sedative-hypnotic degradationproducts. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or0.03 percent by weight of sedative-hypnotic degradation products.

[0029] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0030] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0031] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0032] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

[0033] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mLor 10⁸ particles/mL.

[0034] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhaleable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhaleable particles per second.

[0035] Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

[0036] Typically, the delivered condensation aerosol results in a peakplasma concentration of a sedative-hypnotic in the mammal in less than 1h. Preferably, the peak plasma concentration is reached in less than 0.5h. More preferably, the peak plasma concentration is reached in lessthan 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

[0037] Typically, the delivered condensation aerosol is used to treatinsomnia.

[0038] In another method aspect of the present invention, one ofzaleplon, zolpidem or zopiclone is delivered to a mammal through aninhalation route. The method comprises: a) heating a composition,wherein the composition comprises at least 5 percent by weight ofzaleplon, zolpidem or zopiclone, to form a vapor; and, b) allowing thevapor to cool, thereby forming a condensation aerosol comprisingparticles, which is inhaled by the mammal. Preferably, the compositionthat is heated comprises at least 10 percent by weight of zaleplon,zolpidem or zopiclone. More preferably, the composition comprises atleast 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent,99.5 percent, 99.9 percent or 99.97 percent by weight of zaleplon,zolpidem or zopiclone.

[0039] Typically, the particles comprise at least 5 percent by weight ofzaleplon, zolpidem or zopiclone. Preferably, the particles comprise atleast 10 percent by weight of zaleplon, zolpidem or zopiclone. Morepreferably, the particles comprise at least 20 percent, 30 percent, 40percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97percent by weight of zaleplon, zolpidem or zopiclone.

[0040] Typically, the condensation aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200 μg.

[0041] Typically, the particles comprise less than 10 percent by weightof zaleplon, zolpidem or zopiclone degradation products. Preferably, theparticles comprise less than 5 percent by weight of zaleplon, zolpidemor zopiclone degradation products. More preferably, the particlescomprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of zaleplon,zolpidem or zopiclone degradation products.

[0042] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0043] Typically, at least 50 percent by weight of the aerosol isamorphous in form, wherein crystalline forms make up less than 50percent by weight of the total aerosol weight, regardless of the natureof individual particles. Preferably, at least 75 percent by weight ofthe aerosol is amorphous in form. More preferably, at least 90 percentby weight of the aerosol is amorphous in form.

[0044] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0045] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.2.

[0046] Typically, the delivered aerosol has an inhalable aerosol drugmass density of between 0.5 mg/L and 40 mg/L. Preferably, the aerosolhas an inhalable aerosol drug mass density of between 1 mg/L and 20mg/L. More preferably, the aerosol has an inhalable aerosol drug massdensity of between 1 mg/L and 10 mg/L.

[0047] More preferably, the aerosol has an inhalable aerosol drug massdensity of between 1.5 mg/L and 7.5 mg/L.

[0048] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mLor 10⁸ particles/mL.

[0049] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhaleable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhaleable particles per second.

[0050] Typically, the delivered condensation aerosol is formed at a rategreater than 0.5 mg/second. Preferably, the aerosol is formed at a rategreater than 0.75 mg/second. More preferably, the aerosol is formed at arate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.

[0051] Typically, between 0.5 mg and 40 mg of drug are delivered to themammal in a single inspiration. Preferably, between 1 mg and 20 mg ofdrug are delivered to the mammal in a single inspiration. Morepreferably, between 1 mg and 10 mg of drug are delivered to the mammalin a single inspiration.

[0052] Typically, the delivered condensation aerosol results in a peakplasma concentration of zaleplon, zolpidem or zopiclone in the mammal inless than 1 h. Preferably, the peak plasma concentration is reached inless than 0.5 h. More preferably, the peak plasma concentration isreached in less than 0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterialmeasurement).

[0053] Typically, the delivered condensation aerosol is used to treatinsomnia.

[0054] In a kit aspect of the present invention, a kit for delivering asedative-hypnotic through an inhalation route to a mammal is providedwhich comprises: a) a composition comprising at least 5 percent byweight of a sedative-hypnotic; and, b) a device that forms asedative-hypnotic aerosol from the composition, for inhalation by themammal. Preferably, the composition comprises at least 20 percent, 30percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percentor 99.97 percent by weight of a sedative-hypnotic.

[0055] Typically, the device contained in the kit comprises: a) anelement for heating the sedative-hypnotic composition to form a vapor;b) an element allowing the vapor to cool to form an aerosol; and, c) anelement permitting the mammal to inhale the aerosol.

[0056] In another kit aspect of the present invention, a kit fordelivering zaleplon, zolpidem or zopiclone through an inhalation routeto a mammal is provided which comprises: a) a composition comprising atleast 5 percent by weight of zaleplon, zolpidem or zopiclone; and, b) adevice that forms a zaleplon, zolpidem or zopiclone aerosol from thecomposition, for inhalation by the mammal. Preferably, the compositioncomprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight ofzaleplon, zolpidem or zopiclone.

[0057] Typically, the device contained in the kit comprises: a) anelement for heating the zaleplon, zolpidem or zopiclone composition toform a vapor; b) an element allowing the vapor to cool to form anaerosol; and, c) an element permitting the mammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURE

[0058]FIG. 1 shows a cross-sectional view of a device used to deliversedative-hypnotic aerosols to a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

[0059] Definitions

[0060] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0061] “Aerosol” refers to a suspension of solid or liquid particles ina gas.

[0062] “Aerosol drug mass density” refers to the mass ofsedative-hypnotic per unit volume of aerosol.

[0063] “Aerosol mass density” refers to the mass of particulate matterper unit volume of aerosol.

[0064] “Aerosol particle density” refers to the number of particles perunit volume of aerosol.

[0065] “Amorphous particle” refers to a particle that does not containmore than 50 percent by weight of a crystalline form. Preferably, theparticle does not contain more than 25 percent by weight of acrystalline form. More preferably, the particle does not contain morethan 10 percent by weight of a crystalline form.

[0066] “Condensation aerosol” refers to an aerosol formed byvaporization of a substance followed by condensation of the substanceinto an aerosol.

[0067] “Inhalable aerosol drug mass density” refers to the aerosol drugmass density produced by an inhalation device and delivered into atypical patient tidal volume.

[0068] “Inhalable aerosol mass density” refers to the aerosol massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

[0069] “Inhalable aerosol particle density” refers to the aerosolparticle density of particles of size between 100 nm and 5 micronsproduced by an inhalation device and delivered into a typical patienttidal volume.

[0070] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0071] “Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

[0072] “Rate of inhalable aerosol particle formation” refers to thenumber of particles of size between 100 nm and 5 microns produced by aninhalation device per unit time.

[0073] “Rate of drug aerosol formation” refers to the mass ofaerosolized sedative-hypnotic produced by an inhalation device per unittime.

[0074] “Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

[0075] “Sedative-hypnotic degradation product” refers to a compoundresulting from a chemical modification of a sedative-hypnotic. Themodification, for example, can be the result of a thermally orphotochemically induced reaction. Such reactions include, withoutlimitation, oxidation and hydrolysis.

[0076] “Typical patient tidal volume” refers to 1 L for an adult patientand 15 mL/kg for a pediatric patient.

[0077] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.The term “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

[0078] “Zaleplon” refers toN-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide,which is a free base.

[0079] “Zaleplon” degradation product refers to a compound resultingfrom a chemical modification of zaleplon. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation products is C₁₃H₉N₅ (de-ethylation andde-amidation to provide unsubstituted aniline moiety).

[0080] “Zolpidem” refers toN,N,6-trimethyl-2-p-tolyl-imidazo[1,2-a]pyridine-3-acetamide, which is afree base.

[0081] “Zolpidem” degradation product refers to a compound resultingfrom a chemical modification of zolpidem. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis. Anexample of a degradation product is C₁₆H₁₄N₂O (amide removal).

[0082] “Zopiclone” refers to 4-methyl-1-piperazinecarboxylic acid6-[5-chloro-2-pyridinyl]-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-ylester

[0083] “Zolpiclone” degradation product refers to a compound resultingfrom a chemical modification of zopiclone. The modification, forexample, can be the result of a thermally or photochemically inducedreaction. Such reactions include, without limitation, oxidation andhydrolysis. Examples of degradation products include2-amino-5-chloropyridine and 1-methyl piperazine.

[0084] Formation of Sedative-Hypnotic Containing Aerosols

[0085] Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising a sedative-hypnotic to form a vapor, followed by cooling ofthe vapor such that it condenses to provide a sedative-hypnoticcomprising aerosol (condensation aerosol). The composition is heated inone of four forms: as pure active compound (i.e., pure zaleplon,zolpidem or zopiclone); as a mixture of active compound and apharmaceutically acceptable excipient; as a salt form of the pure activecompound; and, as a mixture of active compound salt form and apharmaceutically acceptable excipient.

[0086] Salt forms of sedative-hypnotics (e.g., zaleplon, zolpidem orzopiclone) are either commercially available or are obtained from thecorresponding free base using well known methods in the art. A varietyof pharmaceutically acceptable salts are suitable for aerosolization.Such salts include, without limitation, the following: hydrochloricacid, hydrobromic acid, acetic acid, maleic acid, formic acid, andfumaric acid salts.

[0087] Pharmaceutically acceptable excipients may be volatile ornonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with the sedative-hypnotic. Classesof such excipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

[0088] Solid supports on which the composition is heated are of avariety of shapes. Examples of such shapes include, without limitation,cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mmthickness and virtually any shape permeated by small (e.g., less than1.0 mm-sized) pores. Preferably, solid supports provide a large surfaceto volume ratio (e.g., greater than 100 per meter) and a large surfaceto mass ratio (e.g., greater than 1 cm² per gram).

[0089] A solid support of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0090] A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

[0091] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Carbon yarns and felts are available fromAmerican Kynol, Inc., New York, N.Y. Chromatography resins such asoctadecycl silane chemically bonded to porous silica are exemplarycoated variants of silica.

[0092] The heating of the sedative-hypnotic compositions is performedusing any suitable method. Examples of methods by which heat can begenerated include the following: passage of current through anelectrical resistance element; absorption of electromagnetic radiation,such as microwave or laser light; and, exothermic chemical reactions,such as exothermic salvation, hydration of pyrophoric materials andoxidation of combustible materials.

[0093] Delivery of Sedative-Hypnotic Containing Aerosols

[0094] Sedative-hypnotic containing aerosols of the present inventionare delivered to a mammal using an inhalation device. Where the aerosolis a condensation aerosol, the device has at least three elements: anelement for heating a sedative-hypnotic containing composition to form avapor; an element allowing the vapor to cool, thereby providing acondensation aerosol; and, an element permitting the mammal to inhalethe aerosol. Various suitable heating methods are described above. Theelement that allows cooling is, in it simplest form, an inert passagewaylinking the heating means to the inhalation means. The elementpermitting inhalation is an aerosol exit portal that forms a connectionbetween the cooling element and the mammal's respiratory system.

[0095] One device used to deliver the sedative-hypnotic containingaerosol is described in reference to FIG. 1. Delivery device 100 has aproximal end 102 and a distal end 104, a heating module 106, a powersource 108, and a mouthpiece 110. A sedative-hypnotic composition isdeposited on a surface 112 of heating module 106. Upon activation of auser activated switch 114, power source 108 initiates heating of heatingmodule 106 (e.g, through ignition of combustible fuel or passage ofcurrent through a resistive heating element). The sedative-hypnoticcomposition volatilizes due to the heating of heating module 106 andcondenses to form a condensation aerosol prior to reaching themouthpiece 110 at the proximal end of the device 102. Air flow travelingfrom the device distal end 104 to the mouthpiece 110 carries thecondensation aerosol to the mouthpiece 110, where it is inhaled by themammal.

[0096] Devices, if desired, contain a variety of components tofacilitate the delivery of sedative-hypnotic containing aerosols. Forinstance, the device may include any component known in the art tocontrol the timing of drug aerosolization relative to inhalation (e.g.,breath-actuation), to provide feedback to patients on the rate and/orvolume of inhalation, to prevent excessive use (i.e., “lock-out”feature), to prevent use by unauthorized individuals, and/or to recorddosing histories.

[0097] Dosage of Sedative-Hypnotic Containing Aerosols

[0098] The dosage amount of sedative-hypnotics in aerosol form isgenerally no greater than twice the standard dose of the drug givenorally. For instance, zaleplon, zolpidem and zopiclone are given orallyat strengths of 5 mg or 10 mg for the treatment of insomnia. Asaerosols, 0.5 mg to 40 mg of the compounds are generally provided perinspiration for the same indication. A typical dosage of asedative-hypnotic aerosol is either administered as a single inhalationor as a series of inhalations taken within an hour or less (dosageequals sum of inhaled amounts). Where the drug is administered as aseries of inhalations, a different amount may be delivered in eachinhalation.

[0099] One can determine the appropriate dose of sedative-hypnoticcontaining aerosols to treat a particular condition using methods suchas animal experiments and a dose-finding (Phase I/II) clinical trial.One animal experiment involves measuring plasma concentrations of drugin an animal after its exposure to the aerosol. Mammals such as dogs orprimates are typically used in such studies, since their respiratorysystems are similar to that of a human. Initial dose levels for testingin humans is generally less than or equal to the dose in the mammalmodel that resulted in plasma drug levels associated with a therapeuticeffect in humans. Dose escalation in humans is then performed, untileither an optimal therapeutic response is obtained or a dose-limitingtoxicity is encountered.

[0100] Analysis of Sedative-Hypnotic Containing Aerosols

[0101] Purity of a sedative-hypnotic containing aerosol is determinedusing a number of methods, examples of which are described in Sekine etal, Journal of Forensic Science 32:1271-1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158-162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

[0102] A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

[0103] The gas or liquid chromatograph discussed above contains adetection system (i.e., detector). Such detection systems are well knownin the art and include, for example, flame ionization, photon absorptionand mass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure ofsedative-hypnotic degradation products.

[0104] Particle size distribution of a sedative-hypnotic containingaerosol is determined using any suitable method in the art (e.g.,cascade impaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

[0105] Inhalable aerosol mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0106] Inhalable aerosol drug mass density is determined, for example,by delivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

[0107] Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size is determined bymeasuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum(from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ6, where Dis a typical particle diameter in the size range (generally, the meanboundary MMADs defining the size range) in microns, φ is the particledensity (in g/mL) and mass is given in units of picograms (g⁻¹²)

[0108] Rate of inhalable aerosol particle formation is determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

[0109] Rate of aerosol formation is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice. The delivery is for a set period of time (e.g., 3 s), and themass of particulate matter collected is determined by weighing theconfined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0110] Rate of drug aerosol formation is determined, for example, bydelivering a sedative-hypnotic containing aerosol into a confinedchamber via an inhalation device over a set period of time (e.g., 3 s).Where the aerosol is pure sedative-hypnotic, the amount of drugcollected in the chamber is measured as described above. The rate ofdrug aerosol formation is equal to the amount of sedative-hypnoticcollected in the chamber divided by the duration of the collection time.Where the sedative-hypnotic containing aerosol comprises apharmaceutically acceptable excipient, multiplying the rate of aerosolformation by the percentage of sedative-hypnotic in the aerosol providesthe rate of drug aerosol formation.

[0111] Utility of Sedative-Hypnotic Containing Aerosols

[0112] The sedative-hypnotic containing aerosols of the presentinvention are typically used for the treatment of insomnia. Other usesfor the aerosols include, without limitation, the following: ananticonvulsant; an anxiolytic; and, a myorelaxant.

[0113] The following examples are meant to illustrate, rather thanlimit, the present invention.

[0114] Zolpidem and zopiclone are commercially available from Sigma(www.sigma-aldrich.com). Zaleplon is available in capsule form (SONATA®)and can be isolated using standard methods in the art.

EXAMPLE 1 Volatilization of Zaleplon

[0115] A solution of 5.5 mg zaleplon in approximately 120 μLdichloromethane was coated on a 3 cm×8 cm piece of aluminum foil. Thedichloromethane was allowed to evaporate. The coated foil was wrappedaround a 300 watt halogen tube (Feit Electric Company, Pico Rivera,Calif.), which was inserted into a glass tube sealed at one end with arubber stopper. Running 60 V of alternating current (driven by linepower controlled by a variac) through the bulb for 7 s afforded zaleplonthermal vapor (including zaleplon aerosol), which collected on the glasstube walls. Reverse-phase HPLC analysis with detection by absorption of225 nm light showed the collected material to be greater than 99% purezaleplon.

EXAMPLE 2 Volatilization of Zolpidem

[0116] A solution of 5.3 mg zolpidem in approximately 120 μLdichloromethane was coated on a 3 cm×8 cm piece of aluminum foil. Thedichloromethane was allowed to evaporate. The coated foil was wrappedaround a 300 watt halogen tube (Feit Electric Company, Pico Rivera,Calif.), which was inserted into a glass tube sealed at one end with arubber stopper. Running 60 V of alternating current (driven by linepower controlled by a variac) through the bulb for 6 s afforded zolpidemthermal vapor (including zolpidem aerosol), which collected on the glasstube walls. Reverse-phase HPLC analysis with detection by absorption of225 nm light showed the collected material to be greater than 99% purezolpidem.

EXAMPLE 3 Volatilization of Zopiclone

[0117] A solution of 3.5 mg zopiclone in approximately 120 μLdichloromethane was coated on a 3 cm×8 cm piece of aluminum foil. Thedichloromethane was allowed to evaporate. The coated foil was wrappedaround a 300 watt halogen tube (Feit Electric Company, Pico Rivera,Calif.), which was inserted into a glass tube sealed at one end with arubber stopper. Running 60 V of alternating current (driven by linepower controlled by a variac) through the bulb for 6 s affordedzopiclone thermal vapor (including zopiclone aerosol), which collectedon the glass tube walls. Reverse-phase HPLC analysis with detection byabsorption of 225 nm light showed the collected material to be greaterthan 99% pure zopiclone.

EXAMPLE 4 Particle Size, Particle Density, and Rate of InhalableParticleFormation of Zolpidem Aerosol

[0118] A solution of 10.7 mg zolpidem in 100 μL dichloromethane wasspread out in a thin layer on the central portion of a 3.5 cm×7 cm sheetof aluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. Both of the openings of the tubewere sealed with parafilm, which was punctured with fifteen needles forair flow. The third opening was connected to a 1 liter, 3-neck glassflask. The glass flask was further connected to a large piston capableof drawing 1.1 liters of air through the flask. Alternating current wasrun through the halogen bulb by application of 90 V using a variacconnected to 110 V line power. Within 1 s, an aerosol appeared and wasdrawn into the 1 L flask by use of the piston, with collection of theaerosol terminated after 6 s. The aerosol was analyzed by connecting the1 L flask to an eight-stage Andersen non-viable cascade impactor.Results are shown in table 1. MMAD of the collected aerosol was 2.9microns with a geometric standard deviation of 2.1. Also shown in table1 is the number of particles collected on the various stages of thecascade impactor, given by the mass collected on the stage divided bythe mass of a typical particle trapped on that stage. The mass of asingle particle of diameter D is given by the volume of the particle,πD³/6, multiplied by the density of the drug (taken to be 1 g/cm³). Theinhalable aerosol particle density is the sum of the numbers ofparticles collected on impactor stages 3 to 8 divided by the collectionvolume of 1 L, giving an inhalable aerosol particle density of 3.9×10⁶particles/mL. The rate of inhalable aerosol particle formation is thesum of the numbers of particles collected on impactor stages 3 through 8divided by the formation time of 6 s, giving a rate of inhalable aerosolparticle formation of 6.4×10⁸ particles/second. TABLE 1 Determination ofthe characteristics of a zolpidem condensation aerosol by cascadeimpaction using an Andersen 8-stage non-viable cascade impactor run at 1cubic foot per minute air flow. Mass Particle size Average particlecollected Number of Stage range (microns) size (microns) (mg) particles0  9.0-10.0 9.5 0.1 2.2 × 10⁵ 1 5.8-9.0 7.4 0.3 1.4 × 10⁶ 2 4.7-5.8 5.250.4 5.3 × 10⁶ 3 3.3-4.7 4.0 0.9 2.7 × 10⁷ 4 2.1-3.3 2.7 1.1 1.1 × 10⁸ 51.1-2.1 1.6 0.8 3.7 × 10⁸ 6 0.7-1.1 0.9 0.4 1.1 × 10⁹ 7 0.4-0.7 0.55 0.22.3 × 10⁹ 8   0-0.4 0.2 0.0 0

EXAMPLE 5 Drug Mass Density and Rate of Drug Aerosol Formation ofZolpidem Aerosol

[0119] A solution of 8.3 mg zolpidem in 100 μL dichloromethane wasspread in a thin layer on the central portion of a 3.5 cm×7 cm sheet ofaluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. Both of the openings of the tubewere sealed with parafilm, which was punctured with fifteen needles forair flow. The third opening was connected to a 1 liter, 3-neck glassflask. The glass flask was further connected to a large piston capableof drawing 1.1 liters of air through the flask. Alternating current wasrun through the halogen bulb by application of 90 V using a variacconnected to 110 V line power. Within seconds, an aerosol appeared andwas drawn into the 1 L flask by use of the piston, with formation of theaerosol terminated after 6 s. The aerosol was allowed to sediment ontothe walls of the 1 L flask for approximately 30 minutes. The flask wasthen extracted with acetonitrile and the extract analyzed by HPLC withdetection by light absorption at 225 nm. Comparison with standardscontaining known amounts of zolpidem revealed that 3.7 mg of >97% purezolpidem had been collected in the flask, resulting in an aerosol drugmass density of 3.7 mg/L. The aluminum foil upon which the zolpidem hadpreviously been coated was weighed following the experiment. Of the 8.3mg originally coated on the aluminum, 7.4 mg of the material was foundto have aerosolized in the 6 s time period, implying a rate of drugaerosol formation of 1.2 mg/s.

1. An aerosol for inhalation therapy, wherein the aerosol comprisesparticles comprising at least 10 percent by weight of asedative-hypnotic.
 2. An aerosol for inhalation therapy, wherein theaerosol comprises particles comprising at least 10 percent by weight ofzaleplon, zolpidem or zopiclone.
 3. The aerosol according to claim 2,wherein the aerosol particles have a mass median aerodynamic diameter ofless than 3 microns.
 4. The aerosol according to claim 2, wherein theparticles comprise less than 2.5 percent by weight of zaleplon, zolpidemor zopiclone degradation products.
 5. The aerosol according to claim 3,wherein the aerosol comprises particles comprising at least 90 percentby weight of zaleplon, zolpidem or zopiclone.
 6. The aerosol accordingto claim 5, wherein the aerosol comprises particles comprising at least97 percent by weight of zaleplon, zolpidem or zopiclone.
 7. A method ofdelivering zaleplon, zolpidem or zopiclone to a mammal through aninhalation route, wherein the route comprises: a) heating a composition,wherein the composition comprises at least 5 percent by weight ofzaleplon, zolpidem or zopiclone, to form a vapor; and, b) allowing thevapor to cool, thereby forming a condensation aerosol comprisingparticles, which is inhaled by the mammal.
 8. The method according toclaim 7, wherein the particles comprise at least 10 percent by weight ofzaleplon, zolpidem or zopiclone.
 9. The method according to claim 7,wherein the aerosol particles have a mass median aerodynamic diameter ofless than 3 microns.
 10. The method according to claim 7, wherein theparticles comprise less than 2.5 percent by weight of zaleplon, zolpidemor zopiclone degradation products.
 11. The method according to claim 9,wherein the aerosol comprises particles comprising at least 90 percentby weight of zaleplon, zolpidem or zopiclone.
 12. The method accordingto claim 11, wherein the aerosol comprises particles comprising at least97 percent by weight of zaleplon, zolpidem or zopiclone.
 13. A kit fordelivering zaleplon, zolpidem or zopiclone through an inhalation routeto a mammal, wherein the kit comprises: a) a composition comprising atleast 5 percent by weight of zaleplon, zolpidem or zopiclone; and, b) adevice that forms a zaleplon, zolpidem or zopiclone aerosol from thecomposition, for inhalation by the mammal and wherein the devicecomprises: a) an element for heating the zaleplon, zolpidem or zopiclonecomposition to form a vapor; b) an element allowing the vapor to cool toform an aerosol; and, c) an element permitting the mammal to inhale theaerosol.